Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models

James A. D. Good, Fang Wang, Oliver Rath, Hung Yi Kristal Kaan, Sandeep K. Talapatra, Dawid Podgorski, Simon P. MacKay, Frank Kozielski

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30 Citations (Scopus)


The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

Original languageEnglish
Pages (from-to)1878-1893
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number5
Early online date11 Feb 2013
Publication statusPublished - 14 Mar 2013


  • optimized
  • s-trityl-L-cysteine-based inhibitors
  • kinesin spindle protein
  • potent in vivo
  • antitumor activity
  • lung cancer
  • xenograft models

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